bims-imicid 2022-02-27 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–02–27
thirty-one papers selected by
Dylan Ryan, University of Cambridge

Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response.
Macrophage metabolism in the intestine is compartment-specific and regulated by the microbiota.
Therapeutic nexus of T cell immunometabolism in improving transplantation immunotherapy.
CD14 regulates the metabolomic profiles of distinct macrophage subsets under steady and activated states.
Metabolic Reprogramming of Myeloid-derived Suppressor Cells in the Tumor Microenvironment.
Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance.
New Developments in T Cell Immunometabolism and Implications for Cancer Immunotherapy.
Therapeutic Metabolic Reprograming Using microRNAs: From Cancer to HIV Infection.
Immunometabolism at the intersection of metabolic signaling, cell fate, and systems immunology.
Itaconate, Arginine, and Gamma-Aminobutyric Acid: A Host Metabolite Triad Protective Against Mycobacterial Infection.
Adipose tissue regulatory T cells: differentiation and function.
Genetic BACH1 deficiency alters mitochondrial function and increases NLRP3 inflammasome activation in mouse macrophages.
Adipose tissue macrophages and atherogenesis - a synergy with cholesterolaemia.
Metformin Inhibits ROS Production by Human M2 Macrophages via the Activation of AMPK.
Mitochondrial Transplantation Enhances Phagocytic Function and Decreases Lipid Accumulation in Foam Cell Macrophages.
Teriflunomide shifts the astrocytic bioenergetic profile from oxidative metabolism to glycolysis and attenuates TNFα-induced inflammatory responses.
Multi-Omic Profiling of Macrophages Treated with Phospholipids Containing Omega-3 and Omega-6 Fatty Acids Reveals Complex Immunomodulatory Adaptations at Protein, Lipid and Metabolic Levels.
In vivo fluorescence lifetime imaging of macrophage intracellular metabolism during wound responses in zebrafish.
AKT2 reduces IFNβ1 production to modulate antiviral responses and systemic lupus erythematosus.
Intravenous Arginine Administration Attenuates the Inflammatory Response and Improves Metabolic Profiles in Diet-Induced Obese Mice after Sleeve Gastrectomy.
Diabetes-Induced Changes in Macrophage Biology Might Lead to Reduced Risk for Abdominal Aortic Aneurysm Development.
CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4.
Fatty acids secreted from head and neck cancer induce M2-like Macrophages.
Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation.
Operational tolerance after hematopoietic stem cell transplantation is characterized by distinct transcriptional, phenotypic, and metabolic signatures.
The Interferon Response Dampens the Usutu Virus Infection-Associated Increase in Glycolysis.
Tcf1 preprograms the mobilization of glycolysis in central memory CD8+ T cells during recall responses.
The Potential of Nrf2 Activation as a Therapeutic Target in Systemic Lupus Erythematosus.
Metabolic Dysfunctions of Intestinal Fatty Acids and Tryptophan Reveal Immuno-Inflammatory Response Activation in IgA Nephropathy.
Enhanced function of vaccine dendritic cells from obese donors upon inhibition of the lipid metabolism.
Gut-derived serotonin and its emerging roles in immune function, inflammation, metabolism and the gut-brain axis.

iScience. 2022 Feb 18. 25(2): 103827

Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response.

Dylan G Ryan, Elena V Knatko, Alva M Casey, Jens L Hukelmann, Sharadha Dayalan Naidu, Alejandro J Brenes, Thanapon Ekkunagul, Christa Baker, Maureen Higgins, Laura Tronci, Efterpi Nikitopolou, Tadashi Honda, Richard C Hartley, Luke A J O'Neill, Christian Frezza, Angus I Lamond, Andrey Y Abramov, J Simon C Arthur, Doreen A Cantrell, Michael P Murphy, Albena T Dinkova-Kostova.

  To overcome oxidative, inflammatory, and metabolic stress, cells have evolved cytoprotective protein networks controlled by nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and its negative regulator, Kelch-like ECH associated protein 1 (Keap1). Here, using high-resolution mass spectrometry we characterize the proteomes of macrophages with altered Nrf2 status revealing significant differences among the genotypes in metabolism and redox homeostasis, which were validated with respirometry and metabolomics. Nrf2 affected the proteome following lipopolysaccharide (LPS) stimulation, with alterations in redox, carbohydrate and lipid metabolism, and innate immunity. Notably, Nrf2 activation promoted mitochondrial fusion. The Keap1 inhibitor, 4-octyl itaconate remodeled the inflammatory macrophage proteome, increasing redox and suppressing type I interferon (IFN) response. Similarly, pharmacologic or genetic Nrf2 activation inhibited the transcription of IFN-β and its downstream effector IFIT2 during LPS stimulation. These data suggest that Nrf2 activation facilitates metabolic reprogramming and mitochondrial adaptation, and finetunes the innate immune response in macrophages.

Keywords:  Biochemistry; Immunology; Proteomics

DOI:  https://doi.org/10.1016/j.isci.2022.103827
Immunology. 2022 Feb 24.

Macrophage metabolism in the intestine is compartment-specific and regulated by the microbiota.

Nicholas A Scott, Melissa A E Lawson, Ryan James Hodgetts, Gwénaëlle Le Gall, Lindsay J Hall, Elizabeth R Mann.

Intestinal macrophages play a vital role in the maintenance of gut homeostasis through signals derived from the microbiota. We previously demonstrated that microbial-derived metabolites can shape the metabolic functions of macrophages. Here, we show that antibiotic-induced disruption of the intestinal microbiota dramatically alters both the local metabolite environment, and the metabolic functions of macrophages in the colon. Broad-spectrum antibiotic administration in mice increased expression of the large neutral amino acid transporter LAT1 and accordingly, amino acid uptake. Subsequently, antibiotic administration enhanced the metabolic functions of colonic macrophages, increasing phosphorylation of components of mammalian/mechanistic target of rapamycin (mTOR) signalling pathways, with increased expression of genes involved in glycolysis and oxidative phosphorylation (OXPHOS), increased mitochondrial function, increased rate of extracellular acidification (ECAR; measure of glycolysis) and increased rate of oxygen consumption (OCR; measure of OXPHOS). Small bowel macrophages were less metabolically active than their colonic counterparts, with macrophage metabolism in the small intestine being independent of the microbiota. Finally, we reveal tissue resident Tim4+ CD4+ macrophages exhibit enhanced fatty acid uptake alongside reduced fatty acid synthesis compared to recruited macrophages. Thus, the microbiota shapes gut macrophage metabolism in a compartment-specific manner, with important implications for monocyte recruitment and macrophage differentiation.

DOI: https://doi.org/10.1111/imm.13461
Int Immunopharmacol. 2022 Feb 18. pii: S1567-5769(22)00105-9. [Epub ahead of print]106 108621

Therapeutic nexus of T cell immunometabolism in improving transplantation immunotherapy.

Shadab Kazmi, Mohammad Afzal Khan, Talal Shamma, Abdullah Altuhami, Abdullah Mohammed Assiri, Dieter Clemens Broering.

  Immunometabolism is a therapeutic strategy to tune immune cells through metabolic reprogramming, which allows immune cells to be differentiated according to their energy requirements. Recent therapeutic strategies targeting immunometabolism suggest that intracellular metabolic reprogramming controls T cell activation, proliferation, and differentiation into effector (Teff) or regulatory (Treg) cells. Immunometabolism is being studied for the treatment of inflammatory diseases, including those associated with solid organ transplantation (SOT). Here, we review immunometabolic regulation of immune cells, with a particular focus on Treg metabolic regulation and liver kinase B1 (LKB1) signaling, which stabilize Tregs and prevent inflammation-associated tissue injuries. All in all, here we discussed how targeting T cell immunometabolism modulates Teff and Treg-mediated immune responses, which can be used to boost Treg differentiation, stability, and ultimately favor immunotolerance in clinical transplants.

Keywords:  Immunometabolism; Immunosuppression; Regulatory T cells

DOI:  https://doi.org/10.1016/j.intimp.2022.108621
Immunobiology. 2022 Feb 17. pii: S0171-2985(22)00017-1. [Epub ahead of print]227(2): 152191

CD14 regulates the metabolomic profiles of distinct macrophage subsets under steady and activated states.

Luana Henrique de Macedo, Camila Oliveira Silva Souza, Luiz Gustavo Gardinassi, Lúcia Helena Faccioli.

  Macrophages play pivotal roles during homeostasis and inflammation. They sense exogenous and endogenous molecular patterns via surface and intracellular receptors, which trigger innate immune responses. CD14 is a co-receptor for lipopolysaccharide (LPS), but also drives macrophage responses to Tityus serrulatus scorpion venom (TsV). Cellular activation is tightly coupled with metabolism that sustain their polarization and generate antimicrobial and signaling molecules. Macrophage's origin and nature of stimulus are critical for their responses, but whether these factors impact macrophage metabolism is unknown. Moreover, the regulation of intracellular metabolism by CD14 has not been assessed. Using an untargeted metabolomics approach, we determined the longitudinal metabolic responses of peritoneal (PMs) and bone marrow derived macrophages (BMDMs) stimulated with LPS and TsV for 12 h. These data revealed alterations on the relative levels of several metabolites and pathways related to amino acids, nucleotides, lipids, and vitamins. Our data suggest activation of selenoamino acid metabolism and increased abundance of selenomethionine in both cell subsets stimulated with LPS. Moreover, the results suggest a differential activity of vitamin B3 metabolism pathway in response to TsV stimulus, with differences on regulation of the relative levels of nicotinamide mononucleotide and deamino-NAD+. CD14 deficiency affects the metabolome of both cell subsets at steady state. Moreover, CD14 was required for arginine consumption in PMs stimulated with LPS, but not TsV or by BMDMs stimulated by both stimuli. Importantly, the data suggest that CD14 mediates the accumulation of lipids in both macrophage subsets stimulated with LPS, providing insights into the potential role of CD14 for the development of metabolic diseases. We conclude that macrophages acquire a spectrum of metabolic profiles that depend on the origin of these cells, the nature of the stimuli and signaling by innate immune receptors.

Keywords:  CD14; Homeostasis; Inflammation; Macrophages; Metabolomics

DOI:  https://doi.org/10.1016/j.imbio.2022.152191
Discov Med. 2021 May-Jun;31(164):31(164): 141-146

Metabolic Reprogramming of Myeloid-derived Suppressor Cells in the Tumor Microenvironment.

Liang Liu, Shuping Huo, Jianghui Liu, Qiaomin Li, Jing Wang.

A large number of studies on the metabolism of immune cells in anti-tumor response have been carried out in recent years. It is proved that metabolic reprogramming can determine the differentiation and functions of immune cells. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells in the tumor microenvironment (TME). They can significantly inhibit the anti-tumor response of T cells and play an important role in promoting tumor growth, metastasis, and invasion. This review summarizes the energy metabolic pathways of MDSCs in the TME, such as fatty acid oxidation (FAO), glycolysis, and amino acids (AAs) metabolism, and highlights the importance of metabolic reprogramming of MDSCs for its immunosuppressive functions.
J Clin Invest. 2022 Feb 24. pii: e148852. [Epub ahead of print]

Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance.

Yanrui Huang, Jenny H Zhou, Haifeng Zhang, Alberto Canfrán-Duque, Abhishek K Singh, Rachel J Perry, Gerald Shulman, Carlos Fernandez-Hernando, Wang Min.

  Brown adipose tissue (BAT), a crucial heat-generating organ, regulate whole-body energy metabolism by mediating thermogenesis. BAT inflammation is implicated in the pathogenesis of mitochondrial dysfunction and impaired thermogenesis. However, the link between BAT inflammation and systematic metabolism remains unclear. Herein, we use mice with BAT deficiency of thioredoxin-2 (TRX2), a protein that scavenges mitochondrial reactive oxygen species (ROS), to evaluate the impact of BAT inflammation on metabolism and thermogenesis and its underlying mechanism. Our results describe that BAT-specific TRX2 ablation improves systematic metabolic performance via enhancing lipid uptake, which protects mice from diet-induced obesity, hypertriglyceridemia, and insulin resistance. TRX2 deficiency impairs adaptive thermogenesis by suppressing fatty acid oxidation. Mechanistically, loss of TRX2 induces excessive mitochondrial ROS, mitochondrial integrity disruption, and cytosolic release of mitochondrial DNA, which in turn activate aberrant innate immune responses in BAT, including the cGAS-STING and the NLRP3 inflammasome pathways. We identify NLRP3 as a key converging point, as its inhibition reverses both the thermogenesis defect and the metabolic benefits seen under nutrient overload in BAT-specific Trx2-deficient mice. In conclusion, we identify TRX2 as a critical hub integrating oxidative stress, inflammation, and lipid metabolism in BAT; uncovering an adaptive mechanism underlying the link between BAT inflammation and systematic metabolism.

Keywords:  Adipose tissue; Inflammation; Innate immunity; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/JCI148852
Cells. 2022 Feb 17. pii: 708. [Epub ahead of print]11(4):

New Developments in T Cell Immunometabolism and Implications for Cancer Immunotherapy.

Nathaniel Oberholtzer, Kristen M Quinn, Paramita Chakraborty, Shikhar Mehrotra.

  Despite rapid advances in the field of immunotherapy, the elimination of established tumors has not been achieved. Many promising new treatments such as adoptive cell therapy (ACT) fall short, primarily due to the loss of T cell effector function or the failure of long-term T cell persistence. With the availability of new tools and advancements in technology, our understanding of metabolic processes has increased enormously in the last decade. Redundancy in metabolic pathways and overlapping targets that could address the plasticity and heterogenous phenotypes of various T cell subsets have illuminated the need for understanding immunometabolism in the context of multiple disease states, including cancer immunology. Herein, we discuss the developing field of T cell immunometabolism and its crucial relevance to improving immunotherapeutic approaches. This in-depth review details the metabolic pathways and preferences of the antitumor immune system and the state of various metabolism-targeting therapeutic approaches.

Keywords:  T cell metabolism; antitumor metabolism; cancer; immunometabolism; immunotherapy

DOI:  https://doi.org/10.3390/cells11040708
Genes (Basel). 2022 Jan 29. pii: 273. [Epub ahead of print]13(2):

Therapeutic Metabolic Reprograming Using microRNAs: From Cancer to HIV Infection.

Mark S Gibson, Cláudia Noronha-Estima, Margarida Gama-Carvalho.

  MicroRNAs (miRNAs) are crucial regulators of cellular processes, including metabolism. Attempts to use miRNAs as therapeutic agents are being explored in several areas, including the control of cancer progression. Recent evidence suggests fine tuning miRNA activity to reprogram tumor cell metabolism has enormous potential as an alternative treatment option. Indeed, cancer growth is known to be linked to profound metabolic changes. Likewise, the emerging field of immunometabolism is leading to a refined understanding of how immune cell proliferation and function is governed by glucose homeostasis. Different immune cell types are now known to have unique metabolic signatures that switch in response to a changing environment. T-cell subsets exhibit distinct metabolic profiles which underlie their alternative differentiation and phenotypic functions. Recent evidence shows that the susceptibility of CD4+ T-cells to HIV infection is intimately linked to their metabolic activity, with many of the metabolic features of HIV-1-infected cells resembling those found in tumor cells. In this review, we discuss the use of miRNA modulation to achieve metabolic reprogramming for cancer therapy and explore the idea that the same approach may serve as an effective mechanism to restrict HIV replication and eliminate infected cells.

Keywords:  HIV; cancer; immunometabolism; metabolism; microRNAs; therapy

DOI:  https://doi.org/10.3390/genes13020273
Cell Mol Immunol. 2022 Feb 21.

Immunometabolism at the intersection of metabolic signaling, cell fate, and systems immunology.

Hongbo Chi.

DOI: https://doi.org/10.1038/s41423-022-00840-x
Front Immunol. 2022 ;13 832015

Itaconate, Arginine, and Gamma-Aminobutyric Acid: A Host Metabolite Triad Protective Against Mycobacterial Infection.

Jin Kyung Kim, Eun-Jin Park, Eun-Kyeong Jo.

  Immune metabolic regulation shapes the host-pathogen interaction during infection with Mycobacterium tuberculosis (Mtb), the pathogen of human tuberculosis (TB). Several immunometabolites generated by metabolic remodeling in macrophages are implicated in innate immune protection against Mtb infection by fine-tuning defensive pathways. Itaconate, produced by the mitochondrial enzyme immunoresponsive gene 1 (IRG1), has antimicrobial and anti-inflammatory effects, restricting intracellular mycobacterial growth. L-arginine, a component of the urea cycle, is critical for the synthesis of nitric oxide (NO) and is implicated in M1-mediated antimycobacterial responses in myeloid cells. L-citrulline, a by-product of NO production, contributes to host defense and generates L-arginine in myeloid cells. In arginase 1-expressing cells, L-arginine can be converted into ornithine, a polyamine precursor that enhances autophagy and antimicrobial protection against Mtb in Kupffer cells. Gamma-aminobutyric acid (GABA), a metabolite and neurotransmitter, activate autophagy to induce antimycobacterial host defenses. This review discusses the recent updates of the functions of the three metabolites in host protection against mycobacterial infection. Understanding the mechanisms by which these metabolites promote host defense will facilitate the development of novel host-directed therapeutics against Mtb and drug-resistant bacteria.

Keywords:  GABA; Mycobacterium tuberculosis; arginine; host defense; innate immunity; itaconate

DOI:  https://doi.org/10.3389/fimmu.2022.832015
Int Rev Immunol. 2022 Feb 25. 1-11

Adipose tissue regulatory T cells: differentiation and function.

Allen N Fooks, Lisa Y Beppu, Adolfo B Frias, Louise M D'Cruz.

  Rising obesity levels, worldwide, are resulting in substantial increases in cardiovascular disease, diabetes, kidney disease, musculoskeletal disorders, and certain cancers, and obesity-associated illnesses are estimated to cause ∼4 million deaths worldwide per year. A common theme in this disease epidemic is the chronic systemic inflammation that accompanies obesity. CD4+ Foxp3+ regulatory T cells residing in visceral adipose tissues (VAT Tregs) are a unique immune cell population that play essential functions in restricting obesity-associated systemic inflammation through regulation of adipose tissue homeostasis. The distinct transcriptional program that defines VAT Tregs has been described, but directly linking VAT Treg differentiation and function to improving insulin sensitivity has proven more complex. Here we review new findings which have clarified how VAT Tregs differentiate, and how distinct VAT Treg subsets regulate VAT homeostasis, energy expenditure, and insulin sensitivity.

Keywords:  Treg; adipose tissue; cytokine; thermogenesis

DOI:  https://doi.org/10.1080/08830185.2022.2044808
Redox Biol. 2022 Feb 10. pii: S2213-2317(22)00037-4. [Epub ahead of print]51 102265

Genetic BACH1 deficiency alters mitochondrial function and increases NLRP3 inflammasome activation in mouse macrophages.

Pooja Pradhan, Vijith Vijayan, Karsten Cirksena, Falk F R Buettner, Kazuhiko Igarashi, Roberto Motterlini, Roberta Foresti, Stephan Immenschuh.

  BTB-and-CNC homologue 1 (BACH1), a heme-regulated transcription factor, mediates innate immune responses via its functional role in macrophages. BACH1 has recently been shown to modulate mitochondrial metabolism in cancer cells. In the current study, we utilized a proteomics approach and demonstrate that genetic deletion of BACH1 in mouse macrophages is associated with decreased levels of various mitochondrial proteins, particularly mitochondrial complex I. Bioenergetic studies revealed alterations of mitochondrial energy metabolism in BACH1-/- macrophages with a shift towards increased glycolysis and decreased oxidative phosphorylation. Moreover, these cells exhibited enhanced mitochondrial membrane potential and generation of mitochondrial reactive oxygen species (mtROS) along with lower levels of mitophagy. Notably, a higher inducibility of NLRP3 inflammasome activation in response to ATP and nigericin following challenge with lipopolysaccharide (LPS) was observed in BACH1-deficient macrophages compared to wild-type cells. Mechanistically, pharmacological inhibition of mtROS markedly attenuated inflammasome activation. In addition, it is shown that inducible nitric oxide synthase and cyclooxygenase-2, both of which are markedly induced by LPS in macrophages, are directly implicated in BACH1-dependent regulation of NLRP3 inflammasome activation. Taken together, the current findings indicate that BACH1 is critical for immunomodulation of macrophages and may serve as a target for therapeutic approaches in inflammatory disorders.

Keywords:  BACH1; Inflammation; Macrophages; Mitochondrial complex 1; Mitochondrial metabolism; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.redox.2022.102265
Physiol Res. 2021 Dec 30. 70(Suppl4): S535-S549

Adipose tissue macrophages and atherogenesis - a synergy with cholesterolaemia.

R Poledne, I Králová Lesná.

Excessive LDL cholesterol concentration together with subclinical inflammation, in which macrophages play a central role, are linked pathologies. The process starts with the accumulation of macrophages in white adipose tissue and the switch of their polarization toward a pro-inflammatory phenotype. The proportion of pro-inflammatory macrophages in adipose tissue is related to the main risk predictors of cardiovascular disease. The cholesterol content of phospholipids of cell membranes seems to possess a crucial role in the regulation of membrane signal transduction and macrophage polarization. Also, different fatty acids of membrane phospholipids influence phenotypes of adipose tissue macrophages with saturated fatty acids stimulating pro-inflammatory whereas omega3 fatty acids anti-inflammatory changes. The inflammatory status of white adipose tissue, therefore, reflects not only adipose tissue volume but also adipose tissue macrophages feature. The beneficial dietary change leading to an atherogenic lipoprotein decrease may therefore synergically reduce adipose tissue driven inflammation.
Biomedicines. 2022 Jan 29. pii: 319. [Epub ahead of print]10(2):

Metformin Inhibits ROS Production by Human M2 Macrophages via the Activation of AMPK.

Rana M Nassif, Elias Chalhoub, Pia Chedid, Margarita Hurtado-Nedelec, Elia Raya, Pham My-Chan Dang, Jean-Claude Marie, Jamel El-Benna.

  Metformin (1,1-dimethylbiguanide hydrochloride) is the most commonly used drug to treat type II diabetic patients. It is believed that this drug has several other beneficial effects, such as anti-inflammatory and anticancer effects. Here, we wanted to evaluate the effect of metformin on the production of reactive oxygen species (ROS) by human macrophages. Macrophages are generated in vivo from circulating monocytes depending on the local tissue environment. In vitro proinflammatory macrophages (M1) and anti-inflammatory macrophages (M2) can be generated by culturing monocytes in the presence of different cytokines, such as GM-CSF or M-CSF, respectively. We show that metformin selectively inhibited human monocyte differentiation into proinflammatory macrophages (M1) without inhibiting their differentiation into anti-inflammatory macrophages (M2). Moreover, we demonstrate that, in response to LPS, M2 macrophages produced ROS, which could be very harmful for nearby tissues, and metformin inhibited this process. Interestingly, metformin with LPS induced activation of the adenosine-monophosphate-activated protein kinase (AMPK) and pharmacological activation of AMPK by AICAR, a known AMPK activator, decreased ROS production, whereas the deletion of AMPK in mice dramatically enhanced ROS production in different types of immune cells. These results suggest that metformin exhibits anti-inflammatory effects by inhibiting the differentiation of human monocytes into M1 macrophages and by limiting ROS production by macrophages via the activation of AMPK.

Keywords:  AMPK; NADPH oxidase; NOX2; ROS; inflammation; macrophage; metformin

DOI:  https://doi.org/10.3390/biomedicines10020319
Biomedicines. 2022 Jan 30. pii: 329. [Epub ahead of print]10(2):

Mitochondrial Transplantation Enhances Phagocytic Function and Decreases Lipid Accumulation in Foam Cell Macrophages.

Soraya Játiva, Priscila Calle, Selene Torrico, Ángeles Muñoz, Miriam García, Ivet Martinez, Anna Sola, Georgina Hotter.

  Macrophages have mechanisms for eliminating cholesterol from cells. If excess cholesterol is not eliminated from the macrophages, then transformation into a foam cell may occur. Foam cells are a hallmark of the atherosclerotic lesions that contribute to the development and rupture of atherosclerotic plaques. Several in vitro and in vivo studies have shown changes in the macrophage phenotype and improved phagocytosis after the acquisition of functional mitochondria. However, the effect of mitochondrial transplantation on promoting phagocytosis and phenotypic changes in lipid-loaded macrophages leading to foam cells has not been studied. We aimed to prove that the transplantation of healthy mitochondria to highly cholesterol-loaded macrophages induces macrophage phagocytosis and reduces the macrophage shift towards foam cells. For this purpose, using a murine macrophage cell line, RAW264.7, we determined if mitochondria transplantation to 7-ketocholesterol (7-KC)-loaded macrophages reduced lipid accumulation and modified their phagocytic function. We evidenced that mitochondrial transplantation to 7-KC-loaded macrophages reestablished phagocytosis and reduced lipid content. In addition, CPT1a expression and anti-inflammatory cytokines were restored after mitochondrial transplantation. We have developed a potential therapeutic approach to restore foam cell functionality.

Keywords:  7-ketocholesterol; CPT1a; foam cell; inflammation; macrophage; phagocytosis

DOI:  https://doi.org/10.3390/biomedicines10020329
Sci Rep. 2022 02 23. 12(1): 3049

Teriflunomide shifts the astrocytic bioenergetic profile from oxidative metabolism to glycolysis and attenuates TNFα-induced inflammatory responses.

Parijat Kabiraj, Ethan M Grund, Benjamin D S Clarkson, Renee K Johnson, Reghann G LaFrance-Corey, Claudia F Lucchinetti, Charles L Howe.

Astrocytes utilize both glycolytic and mitochondrial pathways to power cellular processes that are vital to maintaining normal CNS functions. These cells also mount inflammatory and acute phase reactive programs in response to diverse stimuli. While the metabolic functions of astrocytes under homeostatic conditions are well-studied, the role of cellular bioenergetics in astrocyte reactivity is poorly understood. Teriflunomide exerts immunomodulatory effects in diseases such as multiple sclerosis by metabolically reprogramming lymphocytes and myeloid cells. We hypothesized that teriflunomide would constrain astrocytic inflammatory responses. Purified murine astrocytes were grown under serum-free conditions to prevent acquisition of a spontaneous reactive state. Stimulation with TNFα activated NFκB and increased secretion of Lcn2. TNFα stimulation increased basal respiration, maximal respiration, and ATP production in astrocytes, as assessed by oxygen consumption rate. TNFα also increased glycolytic reserve and glycolytic capacity of astrocytes but did not change the basal glycolytic rate, as assessed by measuring the extracellular acidification rate. TNFα specifically increased mitochondrial ATP production and secretion of Lcn2 required ATP generated by oxidative phosphorylation. Inhibition of dihydroorotate dehydrogenase via teriflunomide transiently increased both oxidative phosphorylation and glycolysis in quiescent astrocytes, but only the increased glycolytic ATP production was sustained over time, resulting in a bias away from mitochondrial ATP production even at doses down to 1 μM. Preconditioning with teriflunomide prevented the TNFα-induced skew toward oxidative phosphorylation, reduced mitochondrial ATP production, and reduced astrocytic inflammatory responses, suggesting that this drug may limit neuroinflammation by acting as a metabolomodulator.

DOI: https://doi.org/10.1038/s41598-022-07024-7
Int J Mol Sci. 2022 Feb 15. pii: 2139. [Epub ahead of print]23(4):

Multi-Omic Profiling of Macrophages Treated with Phospholipids Containing Omega-3 and Omega-6 Fatty Acids Reveals Complex Immunomodulatory Adaptations at Protein, Lipid and Metabolic Levels.

Tatiana Maurício, Susana Aveiro, Sofia Guedes, Diana Lopes, Tânia Melo, Bruno M Neves, Rosário Domingues, Pedro Domingues.

  In recent years, several studies have demonstrated that polyunsaturated fatty acids have strong immunomodulatory properties, altering several functions of macrophages. In the present work, we sought to provide a multi-omic approach combining the analysis of the lipidome, the proteome, and the metabolome of RAW 264.7 macrophages supplemented with phospholipids containing omega-3 (PC 18:0/22:6; ω3-PC) or omega-6 (PC 18:0/20:4; ω6-PC) fatty acids, alone and in the presence of lipopolysaccharide (LPS). Supplementation of macrophages with ω3 and ω6 phospholipids plus LPS produced a significant reprogramming of the proteome of macrophages and amplified the immune response; it also promoted the expression of anti-inflammatory proteins (e.g., pleckstrin). Supplementation with the ω3-PC and ω6-PC induced significant changes in the lipidome, with a marked increase in lipid species linked to the inflammatory response, attributed to several pro-inflammatory signalling pathways (e.g., LPCs) but also to the pro-resolving effect of inflammation (e.g., PIs). Finally, the metabolomic analysis demonstrated that supplementation with ω3-PC and ω6-PC induced the expression of several metabolites with a pronounced inflammatory and anti-inflammatory effect (e.g., succinate). Overall, our data show that supplementation of macrophages with ω3-PC and ω6-PC effectively modulates the lipidome, proteome, and metabolome of these immune cells, affecting several metabolic pathways involved in the immune response that are triggered by inflammation.

Keywords:  LPS; lipidomics; macrophage; metabolomics; omega-3 phospholipid; omega-6 phospholipid; proteomics

DOI:  https://doi.org/10.3390/ijms23042139
Elife. 2022 02 24. pii: e66080. [Epub ahead of print]11

In vivo fluorescence lifetime imaging of macrophage intracellular metabolism during wound responses in zebrafish.

Veronika Miskolci, Kelsey E Tweed, Michael R Lasarev, Emily C Britt, Alex J Walsh, Landon J Zimmerman, Courtney E McDougal, Mark R Cronan, Jing Fan, John-Demian Sauer, Melissa C Skala, Anna Huttenlocher.

  The function of macrophages in vitro is linked to their metabolic rewiring. However, macrophage metabolism remains poorly characterized in situ. Here, we used two-photon intensity and lifetime imaging of autofluorescent metabolic coenzymes, nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD), to assess the metabolism of macrophages in the wound microenvironment. Inhibiting glycolysis reduced NAD(P)H mean lifetime and made the intracellular redox state of macrophages more oxidized, as indicated by reduced optical redox ratio. We found that TNFα+ macrophages had lower NAD(P)H mean lifetime and were more oxidized compared to TNFα- macrophages. Both infection and thermal injury induced a macrophage population with a more oxidized redox state in wounded tissues. Kinetic analysis detected temporal changes in the optical redox ratio during tissue repair, revealing a shift toward a more reduced redox state over time. Metformin reduced TNFα+ wound macrophages, made intracellular redox state more reduced and improved tissue repair. By contrast, depletion of STAT6 increased TNFα+ wound macrophages, made redox state more oxidized and impaired regeneration. Our findings suggest that autofluorescence of NAD(P)H and FAD is sensitive to dynamic changes in intracellular metabolism in tissues and can be used to probe the temporal and spatial regulation of macrophage metabolism during tissue damage and repair.

Keywords:  FLIM; NAD(P)H; cell biology; immunology; immunometabolism; inflammation; macrophages; mouse; optical redox ratio; wound healing; zebrafish

DOI:  https://doi.org/10.7554/eLife.66080
EMBO J. 2022 Feb 22. e108016

AKT2 reduces IFNβ1 production to modulate antiviral responses and systemic lupus erythematosus.

Xin Zheng, Jun Xiao, Qi Jiang, Lingming Zheng, Chang Liu, Chen Dong, Yuxiao Zheng, Peili Ni, Chi Zhang, Fang Zhang, Ruiyue Zhong, Huihua Ding, Qiong Wang, Ying Qiu, Minxia Gao, Jianping Ding, Nan Shen, Bin Wei, Hongyan Wang.

  Interferon regulatory factor 3 (IRF3)-induced type I interferon (I-IFN) production plays key roles in both antiviral and autoimmune responses. IRF3 phosphorylation, dimerization, and nuclear localization are needed for its activation and function, but the precise regulatory mechanisms remain to be explored. Here, we show that the serine/threonine kinase AKT2 interacts with IRF3 and phosphorylates it on Thr207, thereby attenuating IRF3 nuclear translocation in a 14-3-3ε-dependent manner and reducing I-IFN production. We further find that AKT2 expression is downregulated in viral-infected macrophages or in monocytes and tissue samples from systemic lupus erythematosus (SLE) patients and mouse models. Akt2-deficient mice exhibit increased I-IFN induction and reduced mortality in response to viral infection, but aggravated severity of SLE. Overexpression of AKT2 kinase-inactive or IRF3-T207A mutants in zebrafish supports that AKT2 negatively regulates I-IFN production and antiviral response in a kinase-dependent manner. This negative role of AKT2 in IRF3-induced I-IFN production suggests that AKT2 may be therapeutically targeted to differentially regulate antiviral infection and SLE.

Keywords:  AKT2; I-IFN; IRF3; SLE; viral infection

DOI:  https://doi.org/10.15252/embj.2021108016
Metabolites. 2022 Feb 07. pii: 153. [Epub ahead of print]12(2):

Intravenous Arginine Administration Attenuates the Inflammatory Response and Improves Metabolic Profiles in Diet-Induced Obese Mice after Sleeve Gastrectomy.

Ya-Ling Chen, Ming-Tsan Lin, Wan-Hsuan Wang, Sung-Ling Yeh, Chiu-Li Yeh.

  Sleeve gastrectomy (SG) is a bariatric surgery that can effectively reduce weight and improve obesity-associated comorbidities. However, surgical stress intensifies inflammation and imbalanced metabolic profiles. Arginine (Arg) is a nutrient with immunomodulatory and anti-inflammatory properties. This study evaluated the short-term effects of Arg administration on adipocyte inflammation and metabolic alterations in obese mice after SG. Mice were assigned to normal and high-fat diet (HFD) groups. After 16 weeks, the HFD group were divided to sham (SH), SG with saline (SS), or Arg (SA) groups. SS and SA groups were postoperatively injected with saline or Arg via the tail vein and sacrificed at day 1 or 3 after the SG, respectively. Results showed that obesity caused elevated plasma glucose and leptin levels. The SG operation enhanced the expression of inflammatory cytokines and macrophage infiltration in adipose tissues, whereas hepatocyte gene expressions associated with lipid β-oxidation were downregulated. Arg treatment reversed the expressions of β-oxidation-associated genes and reduced lipid peroxide production in the liver. Additionally, adipose tissue expressions of inflammatory chemokines were reduced, while the M2 macrophage marker increased after surgery. The findings suggest that postoperative Arg administration elicited more balanced hepatic lipid metabolism, polarized macrophages toward the anti-inflammatory type, and attenuated adipocyte inflammation shortly after SG.

Keywords:  adipocyte inflammation; hepatic lipid β-oxidation; lipid peroxide; macrophage polarization

DOI:  https://doi.org/10.3390/metabo12020153
Metabolites. 2022 Jan 29. pii: 128. [Epub ahead of print]12(2):

Diabetes-Induced Changes in Macrophage Biology Might Lead to Reduced Risk for Abdominal Aortic Aneurysm Development.

Giulia Chinetti, Joseph Carboni, Joseph Murdaca, Claudine Moratal, Brigitte Sibille, Juliette Raffort, Fabien Lareyre, Elixène Jean Baptiste, Réda Hassen-Khodja, Jaap G Neels.

  Type 2 diabetes patients are less likely to develop an abdominal aortic aneurysm (AAA). Since macrophages play a crucial role in AAA development, we hypothesized that this decrease in AAA risk in diabetic patients might be due to diabetes-induced changes in macrophage biology. To test this hypothesis, we treated primary macrophages obtained from healthy human volunteers with serum from non-diabetic vs. diabetic AAA patients and observed differences in extracellular acidification and the expression of genes involved in glycolysis and lipid oxidation. These results suggest an increase in metabolism in macrophages treated with serum from diabetic AAA patients. Since serum samples used did not differ in glucose content, these changes are not likely to be caused by differences in glycemia. Macrophage functions have been shown to be linked to their metabolism. In line with this, our data suggest that this increase in macrophage metabolism is accompanied by a shift towards an anti-inflammatory state. Together, these results support a model where diabetes-induced changes in metabolism in macrophages might lead to a reduced risk for AAA development.

Keywords:  inflammation; macrophages; metabolism; type 2 diabetes

DOI:  https://doi.org/10.3390/metabo12020128
Cancer Cell. 2022 Feb 15. pii: S1535-6108(22)00036-8. [Epub ahead of print]

CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4.

Peng Liao, Weimin Wang, Weichao Wang, Ilona Kryczek, Xiong Li, Yingjie Bian, Amanda Sell, Shuang Wei, Sara Grove, Jeffrey K Johnson, Paul D Kennedy, Miguel Gijón, Yatrik M Shah, Weiping Zou.

  Tumor cell intrinsic ferroptosis-initiating mechanisms are unknown. Here, we discover that T cell-derived interferon (IFN)γ in combination with arachidonic acid (AA) induces immunogenic tumor ferroptosis, serving as a mode of action for CD8+ T cell (CTL)-mediated tumor killing. Mechanistically, IFNγ stimulates ACSL4 and alters tumor cell lipid pattern, thereby increasing incorporations of AA into C16 and C18 acyl chain-containing phospholipids. Palmitoleic acid and oleic acid, two common C16 and C18 fatty acids in blood, promote ACSL4-dependent tumor ferroptosis induced by IFNγ plus AA. Moreover, tumor ACSL4 deficiency accelerates tumor progression. Low-dose AA enhances tumor ferroptosis and elevates spontaneous and immune checkpoint blockade (ICB)-induced anti-tumor immunity. Clinically, tumor ACSL4 correlates with T cell signatures and improved survival in ICB-treated cancer patients. Thus, IFNγ signaling paired with selective fatty acids is a natural tumor ferroptosis-promoting mechanism and a mode of action of CTLs. Targeting the ACSL4 pathway is a potential anti-cancer approach.

Keywords:  ACSL4; PD-L1; T cell; arachidonic acid; cancer; ferroptosis; immunotherapy; interferon; oleic acid; palmitoleic acid

DOI:  https://doi.org/10.1016/j.ccell.2022.02.003
J Leukoc Biol. 2022 Feb 25.

Fatty acids secreted from head and neck cancer induce M2-like Macrophages.

Marwah M Albakri, Stanley Ching-Cheng Huang, Hammad N Tashkandi, Scott F Sieg.

  Tumor-infiltrating monocytes can mature into Macrophages that support tumor survival or that display antitumor properties. To explore mechanisms steering Macrophage maturation, we assessed the effects of supernatants from squamous cell carcinoma cell lines (FaDu and SCC) on monocyte-derived Macrophage maturation. Purified monocytes were incubated in medium or medium supplemented with supernatants from FaDu and SCC9 or the leukemia monocytic cell line, THP-1. Macrophages were examined for markers of maturation (CD14, CD68), activation (HLA-DR, CD86, IL15R), scavenger receptor (CD36), toll-like receptor (TLR4), M2 marker (CD206), immune checkpoint (PD-L1), and intracellular chemokine expression (IP-10). Compared to other conditions, cells incubated with FaDu or SCC9 supernatants displayed enhanced survival, down-regulation of cell surface HLA-DR, CD86, IL-15R, CD36, and intracellular IP-10 expression, and increased cell surface PD-L1, CD14, and CD206 expression. Despite expressing TLR4 and CD14, Macrophages matured in tumor supernatants failed to respond to stimulation with the canonical TLR4 agonist, LPS. These changes were accompanied by a decrease in intracellular phospho-p38 expression in tumor supernatant conditioned Macrophages. Depletion of fatty acids from tumor supernatants or treatment of cell cultures with an inhibitor of fatty acid oxidation, Etomoxir, reversed a number of these phenotypic changes induced by tumor supernatants. Additionally, Macrophages incubated with either palmitic acid or oleic acid developed similar phenotypes as cells incubated in tumor supernatants. Together, these data suggest that fatty acids derived from tumor cells can mediate the maturation of Macrophages into a cell type with limited pro-inflammatory characteristics.

Keywords:  Fatty acid; Head and neck cancer; M2-like Macrophages; WIP-1; p-38

DOI:  https://doi.org/10.1002/JLB.1A0521-251R
Immunity. 2022 Feb 15. pii: S1074-7613(22)00042-5. [Epub ahead of print]

Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation.

Adi Biram, Jingjing Liu, Hadas Hezroni, Natalia Davidzohn, Dominik Schmiedel, Eman Khatib-Massalha, Montaser Haddad, Amalie Grenov, Sacha Lebon, Tomer Meir Salame, Nili Dezorella, Dotan Hoffman, Paula Abou Karam, Moshe Biton, Tsvee Lapidot, Mats Bemark, Roi Avraham, Steffen Jung, Ziv Shulman.

  Consecutive exposures to different pathogens are highly prevalent and often alter the host immune response. However, it remains unknown how a secondary bacterial infection affects an ongoing adaptive immune response elicited against primary invading pathogens. We demonstrated that recruitment of Sca-1+ monocytes into lymphoid organs during Salmonella Typhimurium (STm) infection disrupted pre-existing germinal center (GC) reactions. GC responses induced by influenza, plasmodium, or commensals deteriorated following STm infection. GC disruption was independent of the direct bacterial interactions with B cells and instead was induced through recruitment of CCR2-dependent Sca-1+ monocytes into the lymphoid organs. GC collapse was associated with impaired cellular respiration and was dependent on TNFα and IFNγ, the latter of which was essential for Sca-1+ monocyte differentiation. Monocyte recruitment and GC disruption also occurred during LPS-supplemented vaccination and Listeria monocytogenes infection. Thus, systemic activation of the innate immune response upon severe bacterial infection is induced at the expense of antibody-mediated immunity.

Keywords:  B cell; LPS; Listeria; Salmonella; bacterial infection; germinal center; inflammation; monocytes

DOI:  https://doi.org/10.1016/j.immuni.2022.01.013
Sci Transl Med. 2022 Feb 23. 14(633): eabg3083

Operational tolerance after hematopoietic stem cell transplantation is characterized by distinct transcriptional, phenotypic, and metabolic signatures.

Laetitia Dubouchet, Helena Todorov, Ruth Seurinck, Nicolas Vallet, Sofie Van Gassen, Aurélien Corneau, Catherine Blanc, Habib Zouali, Anne Boland, Jean-François Deleuze, Brian Ingram, Regis Peffault de Latour, Yvan Saeys, Gérard Socié, David Michonneau.

The mechanisms underlying operational tolerance after hematopoietic stem cell transplantation in humans are poorly understood. We studied two independent cohorts of patients who underwent allogeneic hematopoietic stem cell transplantation from human leukocyte antigen-identical siblings. Primary tolerance was associated with long-lasting reshaping of the recipients' immune system compared to their healthy donors with an increased proportion of regulatory T cell subsets and decreased T cell activation, proliferation, and migration. Transcriptomics profiles also identified a role for nicotinamide adenine dinucleotide biosynthesis in the regulation of immune cell functions. We then compared individuals with operational tolerance and nontolerant recipients at the phenotypic, transcriptomic, and metabolomic level. We observed alterations centered on CD38+-activated T and B cells in nontolerant patients. In tolerant patients, cell subsets with regulatory functions were prominent. RNA sequencing analyses highlighted modifications in the tolerant patients' transcriptomic profiles, particularly with overexpression of the ectoenzyme NT5E (encoding CD73), which could counterbalance CD38 enzymatic functions by producing adenosine. Further, metabolomic analyses suggested a central role of androgens in establishing operational tolerance. These data were confirmed using an integrative approach to evaluating the immune landscape associated with operational tolerance. Thus, balance between a CD38-activated immune state and CD73-related production of adenosine may be a key regulator of operational tolerance.

DOI: https://doi.org/10.1126/scitranslmed.abg3083
Front Cell Infect Microbiol. 2022 ;12 823181

The Interferon Response Dampens the Usutu Virus Infection-Associated Increase in Glycolysis.

Maria Elisabeth Wald, Michael Sieg, Erik Schilling, Marco Binder, Thomas Wilhelm Vahlenkamp, Claudia Claus.

  The mosquito-borne Usutu virus (USUV) is a zoonotic flavivirus and an emerging pathogen. So far therapeutical options or vaccines are not available in human and veterinary medicine. The bioenergetic profile based on extracellular flux analysis revealed an USUV infection-associated significant increase in basal and stressed glycolysis on Vero and with a tendency for basal glycolysis on the avian cell line TME-R derived from Eurasian blackbirds. On both cell lines this was accompanied by a significant drop in the metabolic potential of glycolysis. Moreover, glycolysis contributed to production of virus progeny, as inhibition of glycolysis with 2-deoxy-D-glucose reduced virus yield on Vero by one log10 step. Additionally, the increase in glycolysis observed on Vero cells after USUV infection was lost after the addition of exogenous type I interferon (IFN) β. To further explore the contribution of the IFN response pathway to the impact of USUV on cellular metabolism, USUV infection was characterized on human A549 respiratory cells with a knockout of the type I IFN receptor, either solely or together with the receptor of type III IFN. Notably, only the double knockout of types I and III IFN receptor increased permissiveness to USUV and supported viral replication together with an alteration of the glycolytic activity, namely an increase in basal glycolysis to an extent that a further increase after injection of metabolic stressors during extracellular flux analysis was not noted. This study provides evidence for glycolysis as a possible target for therapeutic intervention of USUV replication. Moreover, presented data highlight type I and type III IFN system as a determinant for human host cell permissiveness and for the infection-associated impact on glycolysis.

Keywords:  2-deoxy-D-glucose; IFNAR; Usutu virus; extracellular acidification rate; extracellular flux analysis; metabolism; oxygen consumption rate

DOI:  https://doi.org/10.3389/fcimb.2022.823181
Nat Immunol. 2022 Feb 21.

Tcf1 preprograms the mobilization of glycolysis in central memory CD8+ T cells during recall responses.

Qiang Shan, Shengen Shawn Hu, Shaoqi Zhu, Xia Chen, Vladimir P Badovinac, Weiqun Peng, Chongzhi Zang, Hai-Hui Xue.

The mechanisms underlying the heightened protection mediated by central memory CD8+ T (TCM) cells remain unclear. Here we show that the transcription factor Tcf1 was required in resting TCM cells to generate secondary effector CD8+ T cells and to clear pathogens during recall responses. Recall stimulation of CD8+ TCM cells caused extensive reprogramming of the transcriptome and chromatin accessibility, leading to rapid induction of glycolytic enzymes, cell cycle regulators and transcriptional regulators, including Id3. This cluster of genes did not require Tcf1 in resting CD8+ TCM cells, but depended on Tcf1 for optimal induction and chromatin opening in recall-stimulated CD8+ TCM cells. Tcf1 bound extensively to these recall-induced gene loci in resting CD8+ TCM cells and mediated chromatin interactions that positioned these genes in architectural proximity with poised enhancers. Thus, Tcf1 preprogramed a transcriptional program that supported the bioenergetic and proliferative needs of CD8+ TCM cells in case of a secondary challenge.

DOI: https://doi.org/10.1038/s41590-022-01131-3
Metabolites. 2022 Feb 06. pii: 151. [Epub ahead of print]12(2):

The Potential of Nrf2 Activation as a Therapeutic Target in Systemic Lupus Erythematosus.

Michelle T Barati, Dawn J Caster.

  Inflammation and oxidative stress are well established in systemic lupus erythematosus (SLE) and are critical to the pathogenesis of autoimmune diseases. The transcription factor NF-E2 related factor 2 (Nrf2) is a central regulator of cellular anti-oxidative responses, inflammation, and restoration of redox balance. Accumulating reports support an emerging role for the regulation of Nrf2 in SLE. These include findings on the development of lupus-like autoimmune nephritis and altered immune cell populations in mice lacking Nrf2, as well as decreased Nrf2 abundance in the dendritic cells of patients with SLE. Nrf2-inducing agents have been shown to alleviate oxidative and inflammatory stress and reduce tissue injury in SLE mouse models. Since Nrf2 expression can be increased in activated T cells, the precise role of Nrf2 activation in different immune cell types and their function remains to be defined. However, targeting Nrf2 for the treatment of diseases associated with oxidative stress and inflammation, such as SLE, is promising. As investigation of Nrf2-inducing agents in clinical trials grows, defining the signaling and molecular mechanisms of action and downstream effects in response to different Nrf2-inducing agents in specific cells, tissues, and diseases, will be critical for effective clinical use.

Keywords:  Nrf2; lupus nephritis (LN); oxidative stress; systemic lupus erythematosus (SLE)

DOI:  https://doi.org/10.3390/metabo12020151
Front Med (Lausanne). 2022 ;9 811526

Metabolic Dysfunctions of Intestinal Fatty Acids and Tryptophan Reveal Immuno-Inflammatory Response Activation in IgA Nephropathy.

Hongwei Wu, Donge Tang, Manhua Yun, Haiping Liu, Shaoxing Huang, Chen Yun, Berthold Hocher, Xinzhou Zhang, Fanna Liu, Lianghong Yin, Yong Dai.

   Background: Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis. Although an important link between intestinal metabolites and immune activity is widely established, the metabolic profile of IgAN is still poorly understood, which severely limits the mechanistic studies and therapy of IgAN.
Methods: The diversity of intestinal flora and relative abundance of metabolites in IgAN patients and healthy subjects were measured by 16s ribosomal RNA gene sequencing combined with liquid chromatography tandem-mass spectrometry. The levels of serum Gd-IgA1, IL-6, IL-10, IL-22, and TNF-a were tested by ELISA. We employed the tryptophan-targeted UHPLC-MRM-MS approach to assess the content of tryptophan metabolites quantitatively.
Results: Intestinal fatty acid levels, mainly unsaturated fatty acids, were observed to be dramatically decreased in IgAN patients. Disorders in linoleic acid and arachidonic acid metabolism, metabolic imbalances of anti-/pro- inflammatory fatty acid metabolites, and intestinal AhR signaling deficiency might reflect the damage of the intestinal mucosal barrier in IgAN patients. In addition, we found that high levels of Gd-IgA1, IL-22, and TNF-α were associated with the activity of the tryptophan-kynurenine metabolic pathway, as well as lower levels of 3-indolepropionic acid. 3-indolepropionic acid, kynurenine, and indoleacrylic acid had synergistic effects on regulating immuno-inflammatory responses in IgAN patients.
Conclusions: The metabolic characteristic of fatty acids and tryptophan in the intestinal system is disturbed in IgAN patients, leading to active immune-inflammatory reactions.

Keywords:  3-indolepropionic acid; IgA nephropathy; fatty acid metabolism; immune; tryptophan metabolism

DOI:  https://doi.org/10.3389/fmed.2022.811526
Clin Transl Med. 2022 Feb;12(2): e557

Enhanced function of vaccine dendritic cells from obese donors upon inhibition of the lipid metabolism.

Chiara Massa, Barbara Seliger.

DOI: https://doi.org/10.1002/ctm2.557
Curr Opin Endocrinol Diabetes Obes. 2022 Apr 01. 29(2): 177-182

Gut-derived serotonin and its emerging roles in immune function, inflammation, metabolism and the gut-brain axis.

Suhrid Banskota, Waliul I Khan.

PURPOSE OF REVIEW: To shed light on the recently uncovered diverse role of serotonin (5-hydroxytryptamine; 5-HT) in the regulation of immune functions, inflammation, metabolism, and gut-brain axis.
RECENT FINDINGS: Peripheral 5-HT which accounts for approximately 95% of the total is largely synthesized in the gut by enterochromaffin cells. Enterochromaffin cells release 5-HT in response to various stimuli including microbial products. Released 5-HT influences secretomotor, sensory and immune functions as well as inflammatory processes in the gut. 5-HT released from enterochromaffin cells enters circulation and is taken up and concentrated in platelets. 5-HT released from the activated platelets interacts with different organs to alter their metabolic activity. 5-HT also serves as a link in the gut-brain axis.
SUMMARY: Emerging evidence regarding the role of peripheral 5-HT in the regulation of various physiological and pathophysiological conditions opens up new targets for researchers to explore and for clinicians to treat and manage different diseases associated with the altered 5-HT signalling.

DOI: https://doi.org/10.1097/MED.0000000000000713